Download The Clinical Pharmacology of Lidocaine

The Clinical Pharmacology of Lidocaine
as an Antiarrhythymic Drug
By KEN A. COLLINSWORTH, M.D., SUMNER M. KALMAN, M.D.,
AND
DONALD C. HARRISON, M.D.
SUMMARY
This article reviews current knowledge about lidocaine, with reference to its chemistry, metabolism, electrophysiology, hemodynamic effects, antiarrhythmic uses, pharmacokinetics, and side effects. The critical
importance of blood levels and their relation to lidocaine's antiarrhythmic and toxic effects is noted, with
special emphasis given to patients with compromised clearance due to heart failure. On the basis of this information, we present our current approach to the clinical use of lidocaine in the treatment of ventricular
arrhythmias, with particular reference to patients with acute myocardial infarction.
Additional Indexing Words:
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Metabolism
Antiarrhythmic actions
Electrophysiology
Side effects
LIDOCAINE was first synthesized in 1943
and was used for many years as a local anesthetic agent.' Its first reported use as an antiarrhythmic drug was in 1950.2 Anesthesiologists subsequently adopted lidocaine for treating arrhythmias
occurring during surgery, and in 1963 its successful
use in treating arrhythmias occurring during and after
cardiac operations was described.3 Lidocaine has since
been used extensively in treating ventricular
arrhythmias, and administered intravenously is probably the most widely used agent for the treatment and
prevention of cardiac arrhythmias after acute myocardial infarction.
Blood levels
pathway (fig. 1) appears to be conversion to monoethylglycinexylidide by oxidative N-de-ethylation
followed by hydrolysis to 2,6-xylidine.' Evidence exists for a cyclic intermediate in the N-de-ethylation reaction.7 A stable cyclic form, N'-ethyl-2-methyl-N'(2,6-dimethylphenyl)-4-imidozolidinine, has also
been isolated from the urine of humans receiving oral
lidocaine.7 Further conversion of 2,6-xylidine to 4hydroxy-2,6-xylidine appears to occur in man, since
the latter compound excreted in urine over a 24-hour
period has accounted for over 70% of an orally administered dose of lidocaine.' A number of other
degradative pathways produce small amounts of 3-hydroxylidocaine, 3-hydroxymonoethylglycinexylidide,
and glycinexylidide, as well as small amounts of the
intermediate compounds in its major metabolic pathway, monoethylglycinexylidide and xylidine.' Hydroxylation of the aromatic nitrogen also occurs,
resulting in the formation of N-hydroxylidocaine and
N-hydroxymonoethylglycinexylidide, both of which
have been identified in the urine of patients given oral
lidocaine.' Lidocaine is a weak base with a pKa' of
7.8510 and up to 10% of lidocaine in unchanged form
may be excreted in the urine, depending on the
urinary pH.'.9 Acid urine results in a larger fraction
being excreted in the urine. Extensive biliary secretion
of lidocaine metabolites occurs in rats, but most of
these metabolites are absorbed in the intestine and
then eliminated via the urine.8 There is no evidence
that biliary secretion and intestinal absorption of
lidoDaine metabolites occur in man.9
Chemistry and Metabolism
The chemical structure of lidocaine is an aromatic
group, 2,6-xylidine, which is coupled to diethylglycine via an amide bond. Lidocaine appears to be
metabolized chiefly by the liver.4 5Studies on hepatic
tissue homogenates have shown that the microsomal
enzyme system is primarily responsible for the hepatic
metabolism of lidocaine.' Its major degradative
From the Divisions of Cardiology and Pharmacology, Stanford
University School of Medicine, Stanford, California.
This work was supported in part by NIH grants nos. HL-5709,
HL-5866, and 1-PO1-HL-15833-01. Dr. Collinsworth was supported
in part by the Bay Area Heart Research Committee.
Dr. Collinsworth's present address is Department of Medicine,
University of California, San Francisco, California 94143.
Address for reprints: Donald C. Harrison, M.D., Chief, Cardiology Division, Stanford University School of Medicine, Stanford,
California 94305.
Received April 14, 1973; revision accepted for publication August
21, 1974.
Circulation, Volume 50, December 1974
Hemodynamic effects
Electrophysiology
The electrophysiologic effects of lidocaine on
1217
~~~~~~~~~~~~COLLINSWORTH ET AL.
1218
1218
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N- HYDROXY- MONOETHYGLYCINEXYLIDIDE
N-HYDROXY LIDOCAINE
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3-HYDROXY LIDOCAINE
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Figure 1
Metabolic pathways of lidocaine degradation.
cardiac tissue have been studied extensively. Though
controversy remains, the results of these studies may
be summarized as follows.
Lidocaine causes a slight decrease in automaticity
(spontaneous phase 4 depolarization) of pacemaker
tissue in rabbit atrial tissue in tissue baths at lidocaine
concentrations of 3 and 5 ggml," and in rabbit
sinioatrial node at 2.34 gg/Mn1.2 Larger decreases in
automaticity than found in atrial tissue occur in
canine Purkinje fibers at extracellular lidocaine concentrations of 2.34 ptg/M1'2 and 5 gg/mL`' These
lidocaine concentrations are in the range of
therapeutic blood levels (1.4 to 6.0 j.g/ml) in man
(discussed below). The diastolic threshold requisite for
depolarization in rabbit atrial tissue is increased at extracellular lidocaine concentrations of 3 and 5
9ig/ml." In humans, the ventricular diastolic
threshold is either slightly increased' or unchanged 14
after 1-2 mg/kg intravenous bolus injection. Spontaneous repetitive discharge after a premature
stimulus is prevented by extracellular lidocaine concentrations of 5 pg/mI in canine ventricular tissue and
10 gg/ml in canine Purkinje tissue."1, 1` Lidocaine increases the ventricular fibrillatory threshold in intact
rabbit hearts at perfusion concentrations of 1.5-6.2
pAg/ml, and in acutely ischemic hearts in dogs, at
blood levels of 1.2-5.5 jtg/ml.
The effect of lidocaine on the duration of cardiac
potential and effective refractory period has
been studied."11 13, 16, 17 The action potential duration
in canine Purkinje fibers is decreased at extracellular
lidocaine concentrations of 2.34 gtg/M1'6' " and 5
gtg/Ml."1 Lidocaine also shortens the action potential
duration in ventricular muscle at extracellular concentrations of 3 ug/in1 in tissue from rabbits" and 2.34
p~g/ml in tissue from dogs.'6,1 A more prominent
effect is noted on Purkinje fibers than on ventricular
muscle. '7
The effective refractory period is relatively
prolonged compared to the action potential duration
in both Purkinje fibers and ventricular muscle.'16
Lidocaine's effect on the maximum rate of depolarization and membrane responsiveness has been the subject of controversy."` The reported differences are
probably due to the extracellular potassium concentrations in the tissue baths at which these two properties are measured.", 16, 18, 19 At physiologic potassium
levels (5.6 mM), the maximum rate of depolarization
and membrane responsiveness in rabbit ventricular
muscle is decreased by extracellular lidocaine concentrations of 3 g.g/ml." Hypokalemic solutions (3.0
MM), however, cause hyperpolarization of the cell
membrane so that tenfold increases in lidocaine concentration are needed before depression of membrane
action
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE
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responsiveness or maximum rate of depolarization occurs.1 Conduction velocity in Purkinje fibers in
hypokalemic (3.0 mM) bath preparations appears to
be slightly decreased by lidocaine concentrations of
5-50 ,g/ml.l3
Atrioventricular (A-V) node and intraventricular
conduction time in man are not significantly changed
after intravenous injections of lidocaine of 1-2
mg/kg.20 However, A-V node conduction time is increased in dogs given high-dose intravenous injections
of lidocaine (5-20 mg/kg).21
These electrophysiologic effects cannot be correlated precisely with lidocaine's antiarrhythmic actions in humans at this time, but can be used to
speculate upon its mode of action in certain specific
instances. Ventricular arrhythmias due to acceleration
of ectopic foci may be responsive to lidocaine because
of its effect on decreasing automaticity by slowing the
rate of spontaneous phase 4 depolarization. Lidocaine
has been shown to abolish the gating function of distal
Purkinje tissue by reducing the nonuniformity of action potential duration in Purkinje tissue, resulting in
more uniform recovery of excitability,'7 and to abolish
slowing of conduction in Purkinje tissue.", 17 Reentrant ventricular arrhythmias may thus be abolished
by lidocaine, due to its effect on action potential
durations resulting in altered conduction velocity and
excitability.
The results reviewed here were obtained mostly
from in vitro animal muscle preparations that were
studied in well-oxygenated baths, in contrast to the in
vivo situation, where arrhythmias possibly originate
from ischemic injured myocardium. Another
difference would be that in vivo the microcirculation
would be perfused, at least partially, whereas no such
perfusion would exist in vitro. This might change the
oxygen availability at different areas in the myocardium, and different lidocaine concentrations at
different areas in the myocardium might exist in both
instances. Similar extensive electrophysiologic studies
with lidocaine in vitro in damaged or ischemic
myocardial tissue have not been reported, though a
recent report has demonstrated that lidocaine does
affect differently the electrophysiologic properties of
normal and ischemic dog Purkinje fibers.22 The
reported differences, in part, may have resulted from
use of tissues from different animal species and thus
reflect species variation in response to lidocaine.
Tissue was used from different areas of myocardium,
which may also have caused different responses to
lidocaine. In addition, different extracellular potassium concentrations, which had previously been
shown to alter the electrophysiologic changes induced
by lidocaine in the same tissue,"' 19 were used in these
experiments. These potassium-related differences
Circulation, Volume 50, December 1974
1219
might have clinical relevance with regard to
lidocaine's antiarrhythmic mechanism and efficacy,
since they were noted at extracellular potassium concentrations which occur in many clinical instances,
i.e., 3mM and 5.6 mM. A summary of the findings of
electrophysiologic effects of lidocaine from several
studies is presented in table 1.
Hemodynamic Effects
The hemodynamic effects of lidocaine have been
studied in isolated muscle preparations, isolated perfused hearts, awake and anesthetized animals, animal
models with acute myocardial infarction, anesthetized
man, and in awake man with acute myocardial infarction.
Lidocaine has been shown to depress the contractility of bath preparations of isolated guinea pig right
ventricular muscle.23 In anesthetized dogs, rapid intravenous injections of lidocaine of 2, 4, and 8 mg/kg
resulted in dose-dependent transient decreases of cardiac output, stroke work, arterial pressure, and
peripheral vascular resistance.24 Heart rate increased
slightly. Awake dogs showed less marked changes,
and when the drug was injected over one minute,
negligible depressant effects were seen. Lidocaine has
caused dose-dependent depression of ventricular contractility as measured by left ventricular dp/dt in
anesthetized dogs when given in i.v. injections of from
0.5 to 30 mg/kg.2' Large doses of lidocaine (i.e., 5
mg/kg) given as a bolus have produced significant
transient depression of ventricular contractility (left
ventricular dp/dt), arterial pressure, heart rate, and
cardiac output in anesthetized dogs with experimental
acute myocardial infarction.26 However, when the
same dogs were given a continuous infusion of 200
,g/kg/min, minimal circulatory changes developed.
When a 2.2 mg/kg i.v. injection was given over one
minute to anesthetized adult human males without
cardiovascular disease, heart rate did not change, and
arterial blood pressure did not decline. In half the
patients, there were actually small increases in the
arterial pressure. In awake patients with heart disease,
rapid i.v. injections of lidocaine, 1 mg/kg over one
minute27 and 1.5 mg/kg over one-half minute,28
caused no significant depression of ventricular function. However, one study has shown, transient
minimal depression of ventricular function in half of
the patients given 100 mg bolus doses.29 The effect of
bolus doses of lidocaine up to 2.0 mg/kg given to
anesthetized patients undergoing cardiac surgery has
been studied.3 Minimal decreases were seen in right
ventricular contractile force as measured by a strain
gauge attached directly to the right ventricle, and no
significant changes in arterial pressure or heart rate
were noted.
COLLINSWORTH ET AL.
1220
Table 1
Electrophysiologic Effects of Lidocaine on Cardiac Muscle
Effect
Electrical threshold
atria (rabbit)
Therapeutic cone.
Toxic conc.
low K
low K slightly
normal K T
niormal K T
Purkinje fiber (canine)
Automaticity
atria (rabbit)
Purkinje fiber (canine)
T
low K -e
low K
low K slightly
iiormal K slightly
low K
inormal K slightly 1
low K i
Action potential duration
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atria (rabbit)
low K
ventricular muscle (rabbit)
low K 1
normal K
low K or I
low K I
low K
normal K
low K I
i lormal K I
low K or
low K I
low K
normal K I
low K - or
low K I
low KT
normal K {
low K I
low K T
low K
normal K i
low K -*
normal K I
low K -low K or slightly
low K I
ventricular muscle (canine)
Purkinje fiber (canine)
Effective refractory per iod
atria (rabbit)
ventricular muscle (canine)
Purkinje fiber (canine)
Maximum rate of depolarizatian
(phase 0)
atria (rabbit)
ventricular muscle (rabbit)
ventricular muscle (canine)
Purkinje fiber (canine)
Conduction velocity
atria (rabbit)
Purkinje fiber (canine)
Cone. = concentration; T = inereased
norrmal K
low K
normal K I
low K 1 or slightly I
= decre ased;
In awake patients with acute myocardial infarction,
bolus doses of lidocaine, 1-2 mg/kg30 and 100 mg,31
caused no significant depression of cardiac output,
heart rate, or arterial pressure. In one patient who
received a 5 mg/min continuous infusion of lidocaine,
a marked fall of arterial pressure was observed and
sinus bradyeardia developed.30 In another study in
patients with acute myocardial infarction, continuous
infusion of lidocaine up to 3 mg/min for up to one
hour caused no significant change in left ventricular
contractility, stroke work index, cardiac output,
arterial pressure, or heart rate.32
Lidocaine appears to cause no, or minimal, decrease
in ventricular contractility, cardiac output, arterial
pressure, or heart rate. This generalization would
seem to apply to normal individuals, patients with cardiac disease, and patients with acute myocardial infarction. With excessive doses, however, marked
T
normal K i
low K I
normal K
low K 1
low K slightly I or I
low K ;
normal K 4
low K 1
= no change.
depression of cardiac function in patients with acute
infarction would likely develop. Extrapolating from
dog studies, rapid intravenous bolus injections of
lidocaine leading to very high blood levels would be
more likely to cause depression of cardiac function
than more slowly administered (1-5 min) bolus injections, and it should always be administered in the
latter way in patients with depressed cardiac function.
Antiarrhythmic Actions
Lidocaine administered intravenously has been
highly effective in terminating ventricular premature
beats and ventricular tachycardia occurring during
general surgery, during and after cardiac surgery,
following acute myocardial infarction, and in the
course of digitalis intoxication. It has also been
suggested for the prevention and treatment of ventricular arrhythmias occurring during cardiac
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE
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catheterization. However, ventricular fibrillation is
best treated by electrical cardioversion, to be followed
by lidocaine infusion.
The general experience has been that lidocaine has
not been very effective in the treatment of atrial
or A-V junctional arrhythmias. In isolated atrial tissue,
poor response of ectopic tachycardias to lidocaine has
been shown.12
Perhaps the most important use for lidocaine after
acute myocardial infarction is to suppress ventricular
premature beats which often occur in the early postinfarction period. Most cases of ventricular tachycardia
and fibrillation after acute infarction are preceded by
ventricular premature beats. On the basis of these
observations, criteria have been developed for the
treatment of ventricular arrhythmias occurring after
acute infarction.32 3 We have recommended suppression of ventricular premature beats when: a) more
than five per minute of unifocal origin occur, b)
R-on-T ventricular premature beats are noted, c) multifocal ventricular premature beats occur, d) two or
more ventricular premature beats in a row occur, i.e.,
short bursts of ventricular tachycardia.34 In addition,
after ventricular tachycardia or fibrillation has been
terminated, lidocaine is administered prophylactically
for 24 hours, in an attempt to prevent the recurrence
of ventricular arrhythmias.
Several studies have been carried out to determine
the maintenance dose of intravenous lidocaine
necessary to prevent ventricular premature beats. In
one study, it was found that ventricular premature
beats above a frequency of five per minute were suppressed or terminated in 80% of patients by a
lidocaine blood level of 1.4 to 6.0 ,g/ml (fig. 2).33 This
level was achieved by constant infusion rates of 20-55
gg/kg/min (1.4-4.0 mg/min in a 70 kg patient) (fig.
3).34 Lower rates are recommended in patients with
overt congestive heart failure or liver failure (see
below.) Under a similar program of treatment, one
coronary care unit reported that occurrence of ventricular tachycardia or fibrillation was extremely
rare. 35 Studies have been performed in which
lidocaine was used in standard therapeutic doses
prophylactically after acute myocardial infarction, in a
random manner. 36, 37 In the patients receiving
lidocaine, the frequency of ventricular arrhythmias of
all types was clearly lower. However, because side
effects from lidocaine administration do occur, we do
not presently advocate usage of this drug for all
patients after myocardial infarction, but instead prefer
to administer lidocaine when premonitory signs of
life-threatening cardiac arrhythmias occur.
Pharmacokinetics
The pharmacokinetics of intravenous lidocaine
Circulation, Volume 50, December 1974
1221
administration has been studied in normal healthy
humans.38 42 After an intravenous bolus of lidocaine,
or after discontinuing a constant infusion, the plasma
concentration changes describe a biphasic curve that
can be fitted into two exponential components (fig. 4).
There is an early rapid fall in concentration, followed
by a later slower decrease in plasma concentration. An
average half-life of about 8 min was found in one
study for the early rapid fall, though considerable
variation was present within the group.38 Another
report placed the average value of half-life at 17
m.42 The half-life of the later slow decrease in
plasma concentration of drug has been reported to
average 108 minutes38 and 87 minutes41 in normal subjects.
The two-compartment open model (fig. 5) has been
formulated to explain the biphasic curve observed for
the plasma disappearance of lidocaine.38 41 The first or
central compartment (CPT 1) includes the intravascular space, though the calculated volume of
distribution exceeds plasma volume.38 The second or
peripheral compartment (CPT 2) is larger. When
equilibration is attained for all tissues, the volume of
distribution exceeds total body water,38 and implies
intracellular concentration of lidocaine. In rats, tissue
lidocaine levels in numerous organs are higher than
blood levels, tending to confirm the intracellular concentration of lidocaine.43
BEFORE LUDOCAINE
AFTER LIDOCAINE
ha
CA
R-R iNTERVAL (msec.)
Figure 2
Interval histograms obtained before therapy (left) and during
treatment (right) with lidocaine, 2 mg/min (32 usg/kg of body
weight/minute). The abscissa of the interval histogram represents
the R-R interval in milliseconds, and the ordinate the number of
beats at a given R-R interval. Lidocaine markedly reduced the
number of premature beats. Total beats in each panel = 160.
[Reprinted with permission of Gianelly et al. and New Engl J
Med33]
r -~ ~ ~/ 0
1222
COLLINSWORTH ET AL.
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Figure 3
Relation between the rate of
infusion of lidocaine and the blood
level of lidocaine in 39 patients
receiving a constant infusion. All
levels were measured after at least
two hours of constant infusion in
, *I
I
.
I
S
~
II
~
~
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patients who were not in severe
congestive heart failure or shock.
The area enclosed within the rectangle is considered to be the effective therapeutic range. [Reprinted
with permission of Harrison et al.
and Mod Treatm34]
1
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10 1
oglKg/min
mg/min
20
'
50
160
701
The two phases for the elimination of lidocaine can
be observed best after a steady-state is achieved and
infusion of lidocaine is stopped. The first rapid phase
is due to changes in distribution of lidocaine within
the two compartments atid hepatic metabolism of that
in the central compartment. The liver extraction ratio
for lidocaine is approximately 70% in individuals with
normal liver function." The second, slower phase of
elimination is dependent at least in part upon the
slower net transfer of drug from the larger peripheral
compartment (CPT 2) to the smaller central compartment. Thus, the influence of the slow phase of
elimination dominates the calculation of half-life,
yielding the value of 87 to 108 min.
Based on the principle that during constant infusion
about five half-life times are required to approach
plateau levels of an infused drug,45 and considering a
half-life of 108 min, up to 9 hours would be required
1B0
5
4
3
2
1
~
401
130
LOG
LIDOCAIN E
CONC.
NORMAL SUBJECTS
(,ug/mi)
B
0.1
120
60
180
240
MINUTES
Figure 4
ELIMINATION
Figure 5
Two-compartment
open model
describing
the
disposition
kinetics
of lidocaine. Drug distributes between compartments one and two
and is eliminated via compartment one. [Reprinted with permission
of Rowland and Thomson and Ann NY Acad Sci38]
A biphasic curve following a single intravenous bolus of 50 mg of
lidocaine. A and B are the zero time intercepts of data plotted on
semi-logarithmic paper, while and ,B are the rapid and slow time
a
respectively. The closed circles represent observed data,
whereas open circles represent derived data. [Figure reprinted with
constants,
permission of Thompson et al. and Am Heart J39]
Circulation, Volume 50, December 1974
1223
PHARMACOLOGY OF LIDOCAINE
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to reach plateau levels of lidocaine. Higher rates of infusion yield higher steady-state levels, but the time to
plateau is unchanged. After discontinuing an infusion
at a steady-state level, the dominant elimination halflife is approximately two hours.
Attempting to reach therapeutic levels (i.e., 1.4-6.0
ug/ml)30,33,34 by using conventional rates of constant
infusion alone (i.e., 20-55 ,ug/kg/min)33 can take
several hours, depending on the rate of infusion.
Constant infusion technique alone, then, would not
acutely provide effective blood levels in lifethreatening arrhythmias. Intravenous injections of
lidocaine can provide therapeutically effective levels
within 1 to 2 min, as indicated by clinical observations
of prompt responses of ventricular arrhythmias30 33 34
and by determination of plasma levels38 after bolus
doses. However, bolus administration alone is not
useful for managing persistent ventricular arrhythmias because lidocaine plasma levels fall rapidly
below the therapeutic level due to rapid clearance
from the central compartment, and ventricular
arrhythmias have been observed to return within 15 to
20 minutes after an injection.30 The practical clinical
approach is to give a bolus dose at the same time constant infusion is initiated, in order to achieve persistent
therapeutic levels from the onset of administration.34
With this approach, it would be expected that an initial peak level would be present followed by a rapid
decline to some minimal level, and followed then by a
slow rise to plateau concentrations. Using the two
compartment model, it has been computed for an
average normal individual that a 160 mg lidocaine i.v.
injection (2.3 mg/kg in a 70 kg person) simultaneously
given at the onset of a 4 mg/min infusion (55
,ug/kg/min in a 70 kg person) would produce initial
blood levels of 2 to 4 gg/ml, followed by a decline to a
minimal level between 1 to 2 ,ug/ml at 20-40 min.4
The lidocaine blood level then rises to plateau levels
of 2 to 4 ,ug/ml (fig. 6). Other investigators have computed similar results and shown by actual
measurements in normal individuals that a 100 mg injection of lidocaine followed by an infusion of 1
mg/min would produce a minimal plasma level of just
over 1 gg/ml.38' 40 Using the regimen of constant infusion following an initial i.v. injection, it is thus possible to maintain therapeutic lidocaine levels at all
times after starting the infusion.
Clinical observations demonstrate an increased incidence of lidocaine toxicity, primarily manifested by
central nervous system disturbances in patients with
severe liver disease46 and severe congestive heart
failure.47 Blood levels in excess of 9 utg/ml are frequently associated with toxic effects,33 48 though toxicity has been noted when blood and plasma levels
have been in the 5-9 ,ug/ml range.33 4 In one patient
Circulation. Volume 50, December 1974
_J
W
W
5.
_J
4
CO.
3
0_)
z
0
0
21-
0
_J
1
2
4
3
5
6
7
8
TIME (hours)
Figure 6
Calculated lidocaine plasma level curves where a 4 mg/min
infusion has been combined with a 40 (A), 80 (B), 160 (C), and 320
(D) mg rapid intravenous dose. [Reprinted with permission of Boyes
and Keenaghan, and Livingstone, Edinburgh79]
with advanced heart failure who was receiving
lidocaine at low doses (i.e., 50 mg followed by 1
mg/min infusion), near toxic levels of lidocaine were
measured at 2 hours39 (fig. 7). If the infusion had been
continued, plateau levels near 12 ,g/ml would
probably have been reached. Another patient in cardiogenic shock had lidocaine plasma levels in excess of
8.8 ,ug/ml at 24 hours while receiving an infusion of
only 0.7 mg/min.0
Higher blood levels of lidocaine due to decreased
PLASMA
TIME (min)
Figure 7
Illustration of the difference in plasma level response to infused
lidocaine in a normal subject and a heart failure subject of similar
size. [Reprinted with permission of Thomson et al. and Am
Heart J39]
COLLINSWORTH ET AL.
1224
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clearance have been demonstrated by infusing
lidocaine and simultaneously measuring cardiac output, hepatic clearance of lidocaine, and hepatic blood
flow in patients with stable congestive heart failure."4
In this study, lidocaine blood levels varied inversely
with cardiac output, with higher blood levels present
in patients with depressed cardiac output. Hepatic
blood flow was linearly related to cardiac output.
Higher blood levels correlated well with the degree of
decreased cardiac output (fig. 8), decreased hepatic
blood flow (fig. 9), and decreased lidocaine clearance.
These data suggest that the clearance of lidocaine during steady-state is primarily limited by hepatic blood
flow. Animal studies have also confirmed the correlation between decreased cardiac output and hepatic
blood flow, resulting in decreased lidocaine clearance
and elevated blood concentrations compared to control animals. 51, 52
3.2
0
3.0
2.8
L
0
-11
E
2.6 I-
0
0
CR
W
1
1
In a study of lidocaine pharmacokinetics in patients
with advanced liver disease, the steady-state volume
of distribution was increased on the average by a factor of nearly two, the central compartment volume of
distribution was unchanged, and the plasma clearance
was decreased by almost half, compared to normal
subjects.40 The half-life of the slow phase of elimination was prolonged. As expected, higher than usual
lidocaine plasma levels were present during constant
infusion. Changes in plasma protein or tissue affinity
for lidocaine have been suggested as the cause for the
increased volume of distribution.40 Reduced liver enzyme activity or reduced hepatic blood flow are other
possible reasons for the decrease in plasma clearance.
Care must be used in extrapolating data from computer models of distribution to man.
However, patients with acute myocardial infarction
often have depressed cardiac output and there may be
a redistribution of blood flow away from the
splanchinic bed during the acute phase. Hepatic blood
flow is reduced disproportionately to the reduction in
flow elsewhere during the acute stages of infarction,
thus causing reduced lidocaine clearance in patients
with acute failure compared with patients with
chronic congestive failure. This possibility is supported by the observation that somewhat higher levels
of lidocaine were present in patients shortly after
acute infarction, compared with later stages of
recovery, when similar rates of infusion were used.'8
1
2.4 p-
1
z
3.4 p
U 2.2
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01
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.
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CARDiAC INDEX (I/min/m2)
Figure 8
The relationship between the arterial lidocaine blood level and the
cardiac index in 16 patients is shown. The dotted vertical line
represents the lowest normal value for cardiac index in our
laboratory of 2.5 L/min/m2. The solid square is the average
lidocaine level and cardiac index for 8 patients with abnormally low
cardiac indices, and the solid triangle the average values for the 8
patients with normal cardiac indices. [Reprinted with permission of
Stenson et al. and Circulation44]
5
1
0
250
1
500
.--
.
750
1000
1250
-.1500
-1-
1750
ESTIMATED HEPATIC BLOOD FLOW (mi/minIm2)
Figure 9
The steady-state arterial lidocaine level related inversely to the
estimated hepatic blood flow in ten patients is illustrated. The solid
square is the average lidocaine level for five patients with hepatic
flows of less than 800 ml/min/m2, and the solid triangle is the
average for five patients with hepatic flows of greater than 800
ml/min/m2. [Reprinted with permission of Stenson et al. and Cir-
culation44]
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE
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Another study has shown higher than expected
steady-state plasma levels of lidocaine (i.e., 1.0-2.5
,ug/ml) in a group of patients with acute infarction
and congestive heart failure receiving lidocaine infusions of 0.7 mg/min.50 The mean plasma half-life in
these patients was prolonged (T-1/2 = 200 min)
following cessation of infusion after steady-state levels
had been achieved. The long half-life was in part attributed to slow release of lidocaine from peripheral
tissues and impaired hepatic clearance, probably due
to diminished perfusion. The plasma clearance of
lidocaine was also reduced in these patients40 and
wide ranges of values were found for the apparent
volume of distribution. Another group of patients with
acute infarction but without severe heart failure have
been studied in a similar manner.53 In these patients,
mean plateau levels of 2.25 ,g/ml were achieved by
constant infusion of lidocaine of 30 ,g/kg/min (i.e.,
2.1 mg/min in a 70 kg person). Infusion alone, not
preceded by a bolus dose, had not provided
therapeutic blood levels by 40 minutes. When a 1
mg/kg injection preceded the infusion, initial
therapeutic levels of approximately 1.4 ,g/ml were
achieved, followed by a transient drop below
therapeutic levels. Subsequently, blood levels rose
slowly to steady-state between 8 and 12 hours. After
discontinuing the infusion at steady-state levels, an
initial plasma half-life of 120 minutes was found. A
later phase was also present with a half-life of approximately ten hours. Calculations have been made
of expected blood levels in patients with acute infarction, based on data from normal individuals41 and the
assumption that the volume of distribution is one-half
of normal in patients with acute infarction.4' 54 An 80
mg injection followed by a 2 mg/min infusion would
be expected to produce eventual lidocaine blood
levels between 2 and 4 ,ug/ml, with minimal levels of
1 to 2 gg/ml between 20 and 30 minutes. These
figures roughly correlate with the data presented
above during actual clinical testing, though the
calculated blood levels are slightly higher.
Therapeutic Dosage
On the basis of these data reviewed above, and our
own experience, dosage recommendations for the use
of lidocaine can be made. In patients with presumed
normal cardiac output and normal hepatic function
and blood flow, an initial injection of 2 mg/kg
followed by a 55 ,ug/kg/min infusion should provide
therapeutic lidocaine plasma levels at all times after
the initial injection. These doses are equivalent to a
140 mg dose and approximately 4 mg/min infusion in
a 70 kg person. In patients with acute infarction or
moderately reduced cardiac output, an initial injecCirculation. Volume 50, December 1974
1225
tion of 1.5 mg/kg, followed by 30 ,ug/kg/min infusion, is recommended. These doses correspond approximately to a 100 mg dose, followed by a 2 mg/min
infusion in a 70 kg person. Another approach would
be to give the two smaller bolus doses of 0.75 mg/kg
each, with the second injection following the first by
about 15 minutes. The drug should always be injected
over several minutes, since very rapid injection might
lead to transiently high plasma levels, with possible
toxic side effects. Slower rates of injection would tend
to prevent such high plasma levels, without reduction
in antiarrhythmic effectiveness. In patients with
markedly reduced cardiac output or shock, we recommend a dose of no more than 0.75 mg/kg, followed by
an infusion of 10-20 ,ug/kg/min. This would correspond approximately to a 50 mg injection, followed by
an infusion of 0.7 to 1.4 mg/min, in a 70 kg person.
Even these doses may be too high in some instances.39' 50 In such critically ill cardiac patients in
whom the use of lidocaine is required, monitoring of
lidocaine plasma levels, if available, should serve as a
guide to the proper dose of lidocaine. Several hours
must elapse before new constant blood levels are approached when increasing or decreasing the rate of infusion. Thus, toxic effects of lidocaine during chronic
infusion might persist for a significant period of time
after stopping the infusion. One half-life time (approximately 2 hours) is needed for a 50% decrease in
the plasma level, so that significantly decreased
plasma levels with reduction in toxic effects would
take more than just a few minutes. If a higher plasma
level of lidocaine during constant infusion is desired to
control an arrhythmia, increasing the rate of administration from 2 to 3 mg/min would require
several hours to reach new steady-state levels. In any
case, significantly increased plasma levels would not
develop acutely. In such an instance, we recommend
an injection of 25 mg or less at the time acutely increased plasma levels are required. This can be
repeated every 15 to 20 minutes as necessary to control the arrhythmia.
Since the clearance of lidocaine may be reduced in
patients with liver disease, with up to 50% reductions
noted in some patients with severe cirrhosis,39 40 the
recommendation has been made for reduction of infusion rates of lidocaine.44 Reduction to one-half the
rates for normal would seem appropriate. However,
individualization of doses should be made based on
plasma level determinations, since lidocaine disposition may vary markedly among patients with liver disease.
Patients with chronic renal disease on hemodialysis
show normal pharmacokinetics of lidocaine with
regard to half-life times, plasma clearance, and
volume of distribution.40 However, lidocaine
COLLINSWORTH ET AL.
1226
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metabolites are excreted almost entirely in the urine,
and some of these metabolites have pharmacologic
and possibly toxic effects (see below). Although there
has been no reported additional incidence of toxic
effects during lidocaine administration in patients
with chronic renal failure,34 this may be due to the
brief period of infusion. Lidocaine metabolites would
probably accumulate in the plasma during long infusions, a collection which might result in toxic effects
even when the plasma levels of lidocaine are not
elevated.Though data are not available on this topic,
caution is urged in patients with renal disease receiving prolonged infusions of lidocaine.
It is a well-known pharmacologic principle that
plasma levels of certain drugs may be altered by the
concomitant use of another or several other drugs.
Patients receiving lidocaine are likely to be receiving a
number of other drugs also, including sedatives,
analgesics, inotropic agents, other antiarrhythmic
agents and anticoagulants. The effect of such drugs on
lidocaine disposition in man has not been determined.
However, some information is available from animal
studies. In vitro studies show that phenobarbital increases lidocaine metabolism, whereas drugs such as
isoniazid and chloramphenicol decrease lidocaine
metabolism,55 presumably by altering liver microsomal enzyme activity. One author has shown that the
liver extraction of lidocaine is markedly increased in
phenobarbital pretreated dogs,56 probably due to
enhanced enzymatic metabolism. A different type of
drug interaction is illustrated by propranolol,
isoproterenol, and glucagon, in which drug-induced
hemodynamic change is the factor that alters another
drug's disposition. Propranolol administered to dogs
results in increased lidocaine levels compared to control, by diminishing cardiac output, hepatic blood
flow, and lidocaine clearance.52 In contrast, glucagon
given to dogs and monkeys57 and isoproterenol given
to monkeys51 cause increased hepatic blood flow and
thereby increased clearance of lidocaine. Whether or
not these animal and in vitro studies apply to
lidocaine disposition and plasma levels in humans is
speculative. Clinical studies are needed for elucidation of drug interactions with lidocaine in humans.
the plasma:erythrocyte ratio is approximately 1.34:1,58
Until recently, lidocaine levels were reported as the
hydrochloride form. Currently, many laboratories are
reporting the base form, which is 80% of the
equivalent hydrochloride form.
Other Routes of Administration
Intramuscular injection of lidocaine has been
suggested in an attempt to treat arrhythmias in
patients with acute infarction or suspected infarction
when they are first seen by a physician outside the
hospital.59 Intramuscular injections of 10% lidocaine
in a 4 mg/kg dose into the deltoid muscle provide
blood levels within the therapeutic range of 1.4 ,g/ml
or greater, persisting for 60 to 120 min after initial injection in all patients with myocardial infarction
tested (fig. 10).34' 60 Injection into the deltoid muscle
provides higher and more rapid blood60 and plasma65
levels than does injection into the gluteal muscle, and
thus the former site is recommended. One study has
shown an average reduction of 75% in the number of
ventricular premature beats after intramuscular
lidocaine injection in patients with acute myocardial
infarction.62 We currently recommend lidocaine, 3 to
4 mg/kg intramuscularly, for patients with acute infarction seen at home by a physician, when premature
beats are detected and bradyeardia is not present.
Orally administered lidocaine has not been shown
to provide effective therapeutic levels (fig. 11).41 63
Since lidocaine is metabolized primarily in the liver, it
is substantially inactivated by passage through the
liver after oral administration. A high incidence of
mild central nervous system side effects has also been
reported after oral administration4' (see below).
LIDOCAINE 4 mg/kgm
3.5
CD,
211
20.5
z
Lidocaine Blood Levels
With the increasing availability of lidocaine assay,
lidocaine therapy can be followed accurately, especially in patients with compromised elimination or
in long-term therapy, allowing accurate adjustment of
lidocaine infusion rates to achieve the desired plasma
level and clinical effect. Lidocaine levels are reported
as either blood or plasma levels. Simultaneously
analyzed samples show that the value obtained for
plasma is about 120% of that obtained for blood, and
0 10 30
O
60
90
120
180
240
TIME POST INJ ECT ION
Figure 10
Blood levels of lidocaine produced by the intramuscular injections
of 4 mg/kg lidocaine into deltoid muscle of six patients following
acute myocardial infarction [Reprinted with permission of Harrison
et al. and Mod Treatm'4]
Circulation, Volume 50, December 1974
PHARMACOLOGY OF LIDOCAINE
1227
LIDOCAINE
PLASMA
LEVEL
ag/M1
E
40
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CJ
t:,
0.5l
20
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urn mu
9
20
0
oto
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0.2
*
2
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30
_i
60
90
120
150
ito
210
TIE (mi n)
Figure 11
Plasma levels of lidocaine following 500 mg of oral doses to subjects
G 0. ( * ) and A.L. (M). Data points represent experimentally determined plasma computer-calculated levels. [Reprinted with permission of Boyes et al. and Clin Pharmacol Ther"']
Lidocaine Resistance
Patients with ventricular arrhythmias resistant to
lidocaine have been reported. A study of such patients
referred to a university hospital has been made.34
Some patients in the study were responsive, but only
to high blood levels greater than 5 ug/ml, and were
refractory to ordinary therapeutic levels (fig. 12).
Other patients were considered truly unresponsive to
lidocaine, even at elevated blood levels of 10 gg/ml
and after toxic central nervous system side effects
begin to appear. (fig. 13). In some of these patients
unresponsive ventricular arrhythmias were due to a
parasystolic foci. On the other hand, other patients in
the study were responsive to lidocaine in the usual
therapeutic range, suggesting that lidocaine administration was inadequate. Also, failure to administer a bolus injection before beginning constant
infusion may result in therapeutically ineffective
blood levels for several hours, resulting in apparent
unresponsiveness.
Side Effects
Serious toxic side effects on the central nervous
system include focal and grand mal seizures, psychosis, and rarely, respiratory arrest.49' 63 Drowsiness,
decreased hearing, paresthesias, disorientation, and
muscle twitching may occur, and some patients
become acutely disturbed and agitated. The treatment of central nervous system side effects includes
Circulation, Volume 50, December 1974
//
U
Q o
Ji C)
.
S
!w
c)
U1'
l1 r
0\
jP
51
0
"
\/
J~~~~~~~
30
60
90
NW,
120
150
minutes
Figure 12
Effect of high dose intravenous infusion of lidocaine on ventricular
premature beats and blood levels is illustrated in this figure. In the
top panel, the number of ventricular premature beats per three
minute block of time are shown for one patient. In the center panel,
the dark solid bar represents the period of intermittent infusion of
lidocaine, 130 gg/kg/min. In the bottom panel, the blood level of
lidocaine achieved during this study is shown. Note that as the
blood level of lidocaine was increased with the intermittent infusion, the frequency of ventricular premature beats decreased to
zero. As the blood level was allowed to fall by stopping the infusion,
the number of ventricular premature beats returned to nearly the
same frequency as had been observed in the control period. This
was permitted to occur on four separate occasions in this patient, in
order to determine the threshold dose of lidocaine and the threshold
blood level necessary to suppress ventricular premature beats.
[Reprinted with permission of Harrison and Alderman and Mod
Treatm34]
withdrawal of lidocaine and administration of
sedatives. Convulsive disorders respond well to intravenous barbiturates or diazepam. True allergic
reactions to lidocaine are probably extremely rare,64 65
though this has been challenged.66
The contribution of the metabolic products of
lidocaine degradation to its toxic effects is not clear.
The N-dealkylation metabolites, monoethylglycinexylidide and glycinexylidide may be responsible for
central nervous system symptoms in some cases.67 In
one patient who was confused and had visual
hallucinations, the lidocaine plasma level was in a low
therapeutic range, while levels of both monoethylglycinexylidide and glycinexylidide were considerably
elevated, suggesting an etiologic relationship between
the elevated levels of these metabolites and the toxic
symptoms.67 These two metabolites are apparently not
pharmacologically inert. Monoethylglycinexylidide
COLLINSWORTH ET AL.
1228
5U)
W
6
*
*
~~~~~~~~TOXICFfFECTS
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z
0
00
30
80
90
120
TIME IN MINUTES
Figure 13
Lack of response of ventricular arrhythmias to high dose lidocaine
infusion. [Reprinted with permission of Harrison and Alderman and
Mod Treatm341
has been shown to have local anesthetic' and antiarrhythmic68 actions.
In addition, monoethylglycinexylidide causes convulsions in animals68' 69 and has approximately
equivalent convulsive activity compared to
lidocaine.69 The convulsive activities of monoethylglycinexylidide and lidocaine are additive.69 Glycinexylidide also has local anesthetic actions.67 While
glycinexylidide causes death in animals before convulsions are seen, it does potentiate the convulsive activities of monoethylglycinexylidide and lidocaine.69
Large bolus doses of lidocaine resulting in toxic
levels can produce bradyeardia and hypotension due
to decreased myocardial function.30 Also, the administration of large doses of lidocaine has been
reported to cause heart block, and second degree
heart block has been reported to be converted to complete heart block by lidocaine.4 33' 70 In complete
heart block, subsidiary pacemakers may be slowed.'4
Sinus bradyeardias may be further slowed or induced
by lidocaine.34 70 Sinus arrest has been reported in the
"sick sinus syndrome" after lidocaine administration
and when used in association with other antiarrhythmic drugs.72 Sinus arrest has been induced in
a patient with acute anterior infarction in normal
sinus rhythm who received large bolus doses of
lidocaine, probably resulting in toxic blood levels.73
However, in a normally conducting heart with a normal sinus rhythm, therapeutic levels of lidocaine
cause little or no decrease in A-V conduction20 and
minimal cardiac slowing.3 Furthermore, His bundle
studies performed in patients with conduction abnormalities have shown that increased levels of block induced by lidocaine are probably the exception and not
the rule. In patients with first degree heart block and
prolonged H-V times, one study has shown no significant effect of lidocaine on H-V times.74 In another
study,75 patients with prolonged A-H and H-V times
and bilateral bundle branch block were given
lidocaine, without subsequent significant change in
A-H or H-V times. In both reports, lidocaine suppressed the patients' ventricular premature beats.
These studies would appear to establish that
therapeutic doses of lidocaine may be used safely in
patients with conduction abnormalities. Although
lidocaine may induce heart block or sinus node
depression, it probably does so infrequently, and
mainly when toxic doses have been given. Either abnormality should not necessarily be a contraindication
to the cautious use of lidocaine. The failure to suppress ventricular arrhythmias by withholding
lidocaine may place the patient at greater risk of subsequent complications than the risk of inducing heart
block or bradycardia by giving lidocaine. Lidocaine
may be safely used in treating ventricular premature
beats in patients with artificial ventricular
pacemakers, without fear of altering pacemaker capture, since the threshold response to artificial pacing
does not seem to be significantly changed by
lidocaine. 14
Acceleration of ventricular response in atrial
tachyarrhythmias after lidocaine administration has
been reported, presumably due to enhanced A-V conduction.76 This would seem paradoxical in view of
most studies which point out either unchanged or
slightly diminished A-V conduction by lidocaine.20 An
increase in the number of ventricular ectopic beats in
patients with acute myocardial infarction has been
reported, using low dose lidocaine infusion.77 In addition, re-entry ventricular beats were increased by
lidocaine in animal models of acute infarction in some
instances in one study.78 These reports of paradoxical
effects of lidocaine would appear to need further confirmation.
Circulation, Volume 50, Decenmber 1974
PHARMACOLOGY OF LIDOCAINE
1229
Acknowledgments
Some of the studies cited were carried out in the Coronary Care
Unit at Stanford University Hospital with the collaboration of Dr.
Alfred Spivack and the nursing staff, and the cooperation of several
former cardiac fellows and faculty, who permitted these studies in
their patients. Finally, we have had the excellent editorial assistance
of Mrs. Dorothy McCain in the preparation of this manuscript.
20.
References
21.
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1. LOFGREN N: Studies on Local Anesthetic Lidocaine, a New
Synthetic Drug. Ivan Halggstrom, Stockholm, 1948
(reprinted by the Marin Press, Worcester, Mass)
2. SOUTHWORTH JL, McKusIcK VA, PEIRCE EC, RAWSON FL:
Ventricular fibrillation precipitated by cardiac catheterization. JAMA 143: 717, 1950
3. HARRISON DC, SPROUSE JC, MoRRnow AG: The antiarrhythmic
properties of lidocaine and procainamide. Circulation 28:
486, 1963
4. HOLLUNGER G: On the metabolism of lidocaine. I. The
properties of the enzyme system responsible for the oxidative
metabolism of lidocaine. Acta Pharmacol (Kobenhavn) 17:
356, 1960
5. SUNC CY, TRUANT AP: The physiologic disposition of lidocaine
and its comparison in some respects with procaine. J Pharmacol Exp Ther 112: 432, 1954
6. HOLLUNGER G: On the metabolism of lidocaine. II. The
biotransformation of lidocaine. Acta Pharmacol
(Kobenhavn) 17: 365, 1960
7. BRECK GD, TRAGER WF: Oxidative N-dealkylation: A Mannich
intermediate in the formation of a new metabolite of
lidocaine in man. Science 173: 544, 1971
8. KEENACHAN JB, BOYES RN: The tissue distribution, metabolism
and excretion of lidocaine in rats, guinea pigs, dogs and man.
J Pharm Pharmacol 150: 454, 1972
9. MATHER LE, THOMAS J: Metabolism of lidocaine in man. Life
Sci 2: 915, 1972
10. ERIKSSON E, GRANBERC P, ORTENGREN B: Study of renal
excretion of prilocaine and lidocaine. Acta Chir Scand (suppl
358) 55, 1966
11. SINGH BW, VAUGHN WILLIAMS EM: Effect of altering potassium
concentration on the action of lidocaine and diphenylhydantoin on rabbit atrial and ventricular muscle. Circ Res 29:
286, 1971
12. MANDEL WJ, BIGGER JT: Electrophysiologic effects of lidocaine
on isolated canine and rabbit atrial tissue. J Pharmacol Exp
Ther 178: 81, 1971
13. DAvis LO, TEMTE JU: Electrophysiologic actions of lidocaine
on canine ventricular muscle and Purkinje fibers. Circ Res
24: 639, 1969
14. RYDEN L, KORSGREN M: The effect of lignocaine on the
stimulation threshold and conduction disturbances in
patients treated with pacemakers. Cardiovasc Res 3: 415,
1969
15. BIGGER JT, HEISSENBUTTEL RH: The use of procainamide and
lidocaine in the treatment of cardiac arrhythmias. Prog Cardiovasc Dis 11: 515, 1969
16. BIGGER JT, MANDEL WJ: Effect of lidocaine on the
electrophysiological properties of ventricular muscle and
Purkinje fibers. j Clin Invest 49: 63, 1970
17. WITTIC J, HARRISON LA, WALLACE AG: Electrophysiological
effects of lidocaine on distal Purkinje fibers of canine heart.
Am Heart J 86: 69, 1973
18. BIGGER JT: Electrophysiologic effects of lidocaine on
Circulation, Volume 50. December 1974
19.
22.
23.
24.
25.
26.
mammalian heart muscle. In Lidocaine in the Treatment of
Ventricular Arrhythmias, edited by SCOTT DB, JULIAN DG.
Livingstone, Edinburgh, 1971, p 43
General discussion, Electrophysiologic effects of lidocaine. In
Lidocaine in the Treatment of Ventricular Arrhythmias,
edited by SCOTT DB, JULIAN DG. Livingstone, Edinburgh,
1971, p 59
ROSEN K, LAU S, WEISS M, DAMATO A: The effect of lidocaine
on atrioventricular and intraventricular conduction in man.
Am J Cardiol 25: 1, 1971
LIEBERMAN N, HARRIS R, KATZ R, LIPSCHRTz H, DOLGIN M,
FISHER V: The effects of lidocaine on the electrical and
mechanical activity of the heart. Am J Cardiol 22: 375, 1968
BRENNAN FJ, WIT AL: Effects of lidocaine on electrophysiological properties of Purkinje fibers surrounding acute
myocardial infarction. Circulation 48 (suppl IV):LV-148,
1973
NELSON DH, HARRISON DC: A comparison of the negative
inotropic effects of procainamide, lidocaine and quinidine.
Physiologist 8: 241, 1965
CONSTANTINO RT, CROCKETT SE, VASKO JS: Cardiovascular
effects and dose response relationships of lidocaine. Circulation 36 (suppl II) 11-89, 1967
ALSTEN WG, MORAN JM: Cardiac and peripheral vascular
effects of lidocaine and procainamide. Am J Cardiol 16: 701,
1965
ROBISON SL, SCHROLL M, HARRISON DC: The circulatory
response to lidocaine in experimental myocardial infarction.
Am J Med Sci 258: 260, 1969
27. BINNION PF, MURTACH G, POLLOCK AM, FLETCHER E: Relation
between plasma lignocaine levels and induced hemodynamic changes. Br Med J 3: 390, 1969
28. GROSSMAN JI, COOPER JA, FRIEDEN J: Cardiovascular effects of
infusion of lidocaine in patients with heart disease. Am J
Cardiol 24: 191, 1969
29. SCHUMACHER RR, LIEBERSON AD, CHILDRESS RH, WILLIAMS JF:
Hemodynamic effects of lidocaine in patients with heart disease. Circulation 37: 965, 1968
30. JEWITT DE, KISHON Y, THOMAS M: Lidocaine in the
management of arrhythmias after myocardial infarction.
Lancet 1: 266, 1968
31. STANNNARD M, SLOMAN G, SANGSTER L: Haemodynamic effects
of lignocaine in acute myocardial infarction. Br Med J 2:
468, 1968
32. RARI-ITOOLA SH, SINNO MZ, LOEB HS, CHUQUIMIA R, ROSEN
KM, GuNNAR RM: Lidocaine infusion in acute myocardial
infarction. Arch Intern Med (Chicago) 128: 416, 1971
33. GIANELLY RE,
DER GROEBEN JO, SPIVACK AP, HARRISON
DC: Effects of lidocaine on ventricular arrhythmias in
patients with coronary heart disease. N Engl J Med 277:
1215, 1967
34. HARRISON DC, ALDERMAN EL: The pharmacology and clinical
use of lidocaine as an antiarrhythmic drug
1972. Mod
Treat 9: 139, 1972
35. LoWN B, FAKHRO AM, HOOD WB, THORN GW: The coronary
care unit. JAMA 199: 188, 1967
36. MORCENSEN L: Ventricular tachyarrhythmias and lignocaine
prophylaxis in acute myocardial infarction: A clinical and
therapeutic study. Acta Med Scand (suppl 513) 1, 1970
37. PITT A, LIPP H, ANDERSON ST: Lignocaine given
prophylactically to patients with acute myocardial infarction. Lancet 1: 612, 1971
38. ROWLAND M, THOMSON PD, GR,CHARD A, MELMON RL:
Disposition kinetics of lidocaine in normal subjects. Ann NY
Acad Sci 179: 383, 1971
39. THONISON PD, ROWVLAND M, MELMON KL: The influence of
VON
-
1230
COLLINSWORTH ET AL.
heart failure, liver disease, and renal failure
on
the disposi-
tion of lidocaine in man. Am Heart J 82: 417, 1971
40. THOMSON PD, MELMON KL, RICHARDSON JA, COHN K,
STEINBRRNN W, CLDIHEE R, ROWLAND M: Lidocaine pharmacokinetics in advanced heart failure, liver disease, and
renal failure in humans. Ann Intern Med 78: 499, 1973
41. BOYES RN, SCOTT DB, JEBSON PJ, GODMAN MJ, JULIAN DG:
Pharmacokinetics of lidocaine in man. Clin Pharmacol Ther
Downloaded from http://circ.ahajournals.org/ by guest on April 28, 2017
12: 105, 1971
42. THOMSON P, ROWLAND M, COHN K, STEINBRUNN W, MELMIAN
KL: Critical differences in the pharmacokinetics of lidocaine
between normal and congestive heart failure patients. (abstr)
Clin Res 17: 140, 1969
43. AKERNIAN B, ASTROm A, Ross A, TEK A: Studies on the
absorption and metabolism of labelled prilocaine and
lidocaine in some animal species. Acta Pharmacol et Toxicol
24: 389, 1966
44. STENSON RE, CONSTANTINO RT, HARRISON- DC: Interrelationship of hepatic blood flow, cardiac output, and blood
levels of lidocaine in man. Circulation 43: 205, 1971
45. GOLDSTEIN A, ARONOw L, KALMAN SM: Principles of Drug
Action. New York, Hoeber, 1968
46. SELDEN R, SASAHARA AA: Central nervous system toxicity
induced by lidocaine. JAMA 202: 908, 1967
47. ANDERSON ST, PITT A: Lignocaine in the management of
ventricular arrhythmias. Med J Austral 1: 208, 1969
48. BRONIACE PR, ROBSON JG: Concentrations of lignocaine in
blood after intravenous, intramuscular, epidural, and endotracheal administration. Anaesthesia 16: 461, 1961
49. FOLDEs FF, MOLLOY RE, MC NALL P, KOLKOL LR: Comparison of toxicity of intravenously given local anaesthetic
agents in man. JAMA 172: 1493, 1960
50. PRESCOTT LF, NIMmo J: Plasma lidocaine concentrations
during and after prolonged infusions in patients with
myocardial infarction. In Lidocaine in the Treatment of
Ventricular Arrhythmias, edited by SCOTT DB, JULIAN DG.
Edinburgh, Livingstone, 1970, p 168
51. BENOWXITZ N, ROWLAND M, FORSYTH R, MELMON KL:
Circulatory influences on lidocaine disposition. (abstr) Clin
Res 21: 467, 1973
52. BRANCH RA, SHAND DG, WILKINSON GR, NIES AS: The
reduction of lidocaine clearance by dl-propranolol. An example of hemodynamic drug interaction. J Pharmacol Exp Ther
184: 515, 1973
53. HAYES AH JR: Intravenous infusion of lidocaine in the control
of ventricular arrhythmias. In Lidocaine in the Treatment of
Ventricular Arrhythmias, edited by SCOTT DB, JULIA.N DG.
Edinburgh, Livingstone, 1970, p 189
54. SC OTT DB, JEBSON PJ, VELLANTI CU, JULIAN- DG: Plasma levels
of lignocaine after intramuscular injection. Lancet 21: 1209,
1968
55. HEINONIN J: Influence of some drugs on toxicity and rate of
metabolism of lidocaine and mepivacaine. Ann Med Exp
Biol Fenn 44 (suppl 3): 1, 1966
56. DIFAzIO CA, BROWN RB: Lidocaine metabolism in normal and
phenobarbital pre-treated dogs. Anesthesiology 36: 238,
1972
57. NIES AS, SHAND DG, BRAN-CH RA: Flow-dependent hepatic
drug elimination. The basis for hemodynamic drug interaction. (abstr) Clin Res 21: 471, 1973
58. ERIKSSON E, ENCLESSON S, WAHLQVIST S, ORTENGREN B: Study
59.
60.
61.
62.
63.
64.
of the intravenous toxicity in man and some in vitro studies
on the distribution and adsorbability. Acta Chir Scand
(suppl) 358: 25, 1966
SCOTT DB, JEBSON PJ, VELLANI CW, JULIAN DG: Plasma
lignocaine levels after intravenous and intramuscular injection. Lancet 1: 41, 1970
ZENER JZ, KERBER RE, SPIVACK AP, HARRISON DC: Blood
lidocaine levels and kinetics following high dose intramuscular administration. Circulation 47: 984, 1973
COHEN L, ROSENTHAL J. HORN-ED D, ATKINS J, MATTHEWXS 0,
SARNOFF S: Plasma levels of lidocaine after intramuscular
administration. Am J Cardiol 29: 520, 1972
FEH-MERS M, DUNNING A: Intramuscularly and orally
administered lidocaine in the treatment of ventricular
arrhythmias in acute myocardial infarction. Am J Cardiol 29:
514, 1972
FRIEDEN J: Antiarrhythmic drugs. Part VI. Lidocaine as an
antiarrhythmic agent. Am Heart J 70: 713, 1965
TODD DP: More about the '-allergic reaction to lidocaine."
Anesthesiology 32: 284, 1970
65. WELLINS SL: Hypersensitivity to lidocaine hydrochloride. Oral
Surg 28: 761, 1969
66. LEHNER T: Lidocaine hypersensitivity. Lancet 1: 1245, 1971
67. STRONCG JM, PARKER M, ATKINSON AJ: Identification of
glycinexylidide in patients treated with intravenous
lidocaine. J Clin Pharmacol 14: 67, 1973
68. SMIITH ER, DUCE BR: The acute antiarrhythmic and toxic
effects in mice and dogs of 2-ethylamino-2'6'-acetoxylidine
(L-86), a metabolite of lidocaine. J Pharmacol Exp Ther 179:
580, 1971
69. BLU NIER J, STRONC JM, ATKINSON- AJ: The convulsant potency of
lidocaine and its N-dealkylated metabolites. J Pharmacol
Exp Ther 186: 31, 1973
70. LICHSTEIN E, CHADDA KD, GCPTA PK: Atrioventricular block
with lidocaine therapy. Am J Cardiol 31: 277, 1973
71. LIPPESTAD CT: Production of sinus arrest. Br Med J 1: 537,
1971
72. JERESATY RM, KAHN AH, LANDRY AB: Sinoatrial arrest due to
lidocaine in a patient receiving quinidine. Chest 61: 683,
1972
73. CHENC TO, WADHWA K: Sinus standstill following intravenous
lidocaine administration. JAMA 223: 790, 1973
74. BEKHERT S, MURTACH JG, MORTON P, FLETCHER E: Effect of lignocaine on conducting system of human heart. Br Heart J
35: 305, 1973
75. KuNKEL FW, ROWLAND R, SCHEINNIAN MM: Effects of
intravenous lidocaine infusion on atrioventricular and intraventricular conduction in patients with bilateral bundle
branch block. Circulation 48 (suppl II): IV-188, 1973
76. MARRIOTT HJL, BIEZA CF: Alarming ventricular acceleration
after lidocaine administration. Chest 61: 682, 1972
77. GEDDES JS, WEBB S, PANTRIDGE JF: Limitations of lignocaine in
control of early ventricular dysrhythmias complicating acute
myocardial infarction. Br Heart J 34: 964, 1972
78. GANIBLE OW, COHEN K: Effect of antiarrhythmic drugs on
ventricular re-entry and automaticity in experimental
myocardial infarction. Circulation 44 (suppl II):II-43, 1971
79. BOYES RN, KEENACHAN JB: Some aspects of the metabolism and
distribution of lidocaine in rats, dogs, and man. In Lidocaine
in the Treatment of Ventricular Arrhythmias, edited by
SC OTT DB, JULIAN- DC. Edinburgh, Livingstone, 1971, p 140
Circulation, Volume 50, December 1974
The Clinical Pharmacology of Lidocaine as an Antiarrhythymic Drug
KEN A. COLLINSWORTH, SUMNER M. KALMAN and DONALD C. HARRISON
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Circulation. 1974;50:1217-1230
doi: 10.1161/01.CIR.50.6.1217
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